It is an object of the invention to provide the novel compounds of formulae I and IA and a novel process and novel intermediates for their preparation.
It is another object of the invention to provide novel hormonal compositions and novel methods of inducing hormonal reactions in warm-blooded animals.
These and other objects and advantages of the invention will become obvious from the following detailed description.
The novel compounds of the invention are 19-nor-steroids of the formula 
wherein the A and B rings have a structure selected from the group consisting of 
are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, R3 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and acyl of an organic carboxylic acid of 1 to 7 carbon atoms, R17 and Rxe2x80x217 together form xe2x95x90O or R17 is xe2x80x94OH or acyloxy and Rxe2x80x217 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and alkenyl and alkynyl of 2 to 8 carbon atoms, all optionally substituted, X is selected from the group consisting of xe2x80x94CH2xe2x80x94 or xe2x80x94CH2Oxe2x80x94, arylene and arylenoxy linked to the C ring through a carbon atom, Y is selected from the group consisting of a simple bond and saturated and unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with at least one member of the group consisting of arylene, xe2x80x94Oxe2x80x94 and optionally oxidized xe2x80x94Sxe2x80x94 and optionally terminated with aryl, Z is a simple bond or xe2x80x94CH2Oxe2x80x94 linked to Y by a carbon atom, RA and RAxe2x80x2 being individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of aryl, alkylamino, dialkylamino, xe2x80x94OH, halogen and esterified carboxyl or RA and RAxe2x80x2 taken together with the nitrogen to which they are attached form 5 to 6 ring heterocycle optionally containing at least one heteroatom selected from the group consisting of xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 and xe2x80x94Nxe2x80x94 optionally substituted with alkyl of 1 to 4 carbon atoms with the proviso 1) that both RA and RAxe2x80x2 are not hydrogen, and 2) when Z and Y are both simple bonds, X is not xe2x80x94CH2xe2x80x94 or xe2x80x94CH2Oxe2x80x94, A) wherein n is 1, K is oxygen, R18 is xe2x80x94OH or optionally salified 
RBxe2x80x2 is methyl, RB is isopropyl or n-butyl or heptafluorobutyl, Xxe2x80x2 is selected from the group consisting of methylene, phenylene and phenoxy attached to the steroid by a carbon atom, Yxe2x80x2 is selected from the group consisting of xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)8xe2x80x94, xe2x80x94(CH2)5xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94(CH2)qxe2x80x94Oxe2x80x94xe2x80x94CH2xe2x80x94 and 
q is an integer from 5 to 7, nxe2x80x2 is 0, 1 or 2 and Z is a simple bond and B) wherein n is 1 or 2, K is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, R18 and Rxe2x80x218 form xe2x95x90O or R18 is xe2x80x94OH or acyloxy, and Rxe2x80x218 is selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl and alkynyl of up to 8 carbon atoms, Xxe2x80x2 is selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, arylene and arylenoxy and arylenethio connected to the steroid by a carbon atom, Yxe2x80x2 is selected from the group consisting of a simple bond and optionally unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with arylene or xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 and optionally terminated with arylene, Zxe2x80x2 is a simple bond with the proviso that when Yxe2x80x2 and Zxe2x80x2 are both a simple bond, Xxe2x80x2 is not xe2x80x94CH2xe2x80x94 or xe2x80x94CH2Oxe2x80x94 and RB and Rxe2x80x2B are individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms optionally substituted with a member of the group consisting of aryl, alkylamino, dialkylamino, xe2x80x94OH, halogen and esterified carboxy or taken together with the nitrogen to which they are attached form an optionally unsaturated 5- or 6-member heterocycle optionally containing at least one additional heteroatom of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or nitrogen optionally substituted with a member of the group consisting of alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 10 carbon atoms with the proviso that at least one of RB and Rxe2x80x2B is not hydrogen and at least one of the following conditions is met, n is 2 or K is xe2x80x94Sxe2x80x94 or Xxe2x80x2 is arylenethio attached to the steroid by a carbon atom or RB and Rxe2x80x2B with the nitrogen is a 5- or 6-member heterocycle substituted by aryl or aralkyl.
Examples of R3, R2 and/or Rxe2x80x22 as alkyl are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl and isobutyl, preferably methyl. Examples of R3 as acyl are acetyl, propionyl, butyryl and benzoyl.
When R17 or R18 is an acyloxy, it is derivative of an aliphatic or cycloaliphatic carboxylic acid, saturated or unsaturated and especially alkanoic acids such as for example, acetic acid, propionic acid, butyric acid or isobutyric acid, valeric acid or undecylic acid; a hydroxyalkanoic acid such as hydroxyacetic acid; cycloalkylcarboxylic acids or cycloalkylalkanoic acids such as cyclopropylcarboxylic acid, cyclopentylcarboxylic acid or cyclohexyl carboxylic acid, cyclopentyl or cyclohexyl acetic acid or propionic acid, benzoic acid, salicylic acid or a phenylalkanoic acid such as phenylacetic acid or phenylpropionic acid, an amino acid such as diethylaminoacetic acid or aspartic acid or formic acid. It is preferably a derivative of acetic acid, propionic acid, butyric acid or butanedioic acid.
When R17 or R18 is alkyl, it is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl and most preferably, methyl.
When R17 or R18 is alkenyl, it is preferably vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl and most preferably vinyl or propenyl. When R17 or R18 is alkynyl, it is preferably ethynyl, propynyl, propargyl, butynyl or isobutynyl and most preferably ethynyl or propynyl.
The expression optionally substituted applied to the alkyl, alkenyl or alkynyl includes at least one member of the group consisting of halogen, such as fluorine, chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino or methyl ethylamino, each of the dialkylaminos being optionally in the oxidized form; aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylaminomethyl or ethyl, dialkylaminoalkoxy such as dimethylaminoethoxy, optionally acylated hydroxyl, for example acetoxy or 
in which n=2 to 5, such as acetyl, propionyl, butyryl, benzoyl, free or esterified carboxy and alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyano, trifluoromethyl, aryl such as phenyl, furyl, thienyl or aralkyl such as benzyl, these being optionally substituted by alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or by alkoxy, alkylthio, alkylamino or di-alkylamino indicated above.
When X or Xxe2x80x2 is arylene it is preferably phenylene and when X or Xxe2x80x2 is arylenoxy, it is preferably phenylenoxy.
When Y or Yxe2x80x2 is saturated or unsaturated linear or branched aliphatic chain, it can be methylene, ethylene, propylene, isopropylene, butylene, isobutylene or tert.-butylene, n-pentylene, n-hexylene, 2-methyl pentylene, 2,3-dimethyl butylene, n-heptylene, 2-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 3-ethylpentylene, n-octylene, 2,2-dimethylhexylene, 3,3-dimethylhexylene, 3-methyl 3-ethylpentylene, nonylene, 2,4-dimethyl heptylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-penta-decylene, n-hexadecylene n-heptadecylene or n-octadecylene, preferably n-nonylene or n-decylene. Equally it can be one of the following; vinylene, isopropylene, allylene, 2-methylallylene or isobutenylene, and when the chain is interrupted or terminated by one or more arylenes, it is preferably phenylene, it being understood that terminated relates to anyone of the two extremities of Y or Yxe2x80x2.
When RA or Rxe2x80x2A or RB or Rxe2x80x2B is alkyl, it can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl.
The aforementioned radicals can be substituted by one or more aryl such as phenyl, furyl, thienyl, preferably phenyl; by one or more alkylamino or dialkylamino such as dimethylamino or by one or more esterified carboxyl such as methoxycarbonyl or an ethoxycarbonyl, by one or more halogen atoms for example, fluorine, chlorine or bromine. 2,2,3,3,4,4,4-hepta fluorobutyl or 2-chloro-2-methylpropyl can notably be cited.
When RA and Rxe2x80x2A or RB and Rxe2x80x2B form with the nitrogen atom to which they are linked a heterocycle with 5 to 6 links, it is a saturated heterocycle, preferably pyrrolidine or piperidine optionally substituted by alkyl such as methyl, ethyl, propyl or isopropyl, preferably methyl or ethyl or an unsaturated heterocycle, preferably pyrrole or pyridine optionally substituted by alkyl such as methyl, optionally containing another heteroatom, preferably morpholine, piperazine or pyrimidine, optionally substituted by alkyl, preferably methyl or ethyl.
The preferred compounds of formula I of the invention are those wherein the A and B rings are 
and those wherein A and B are 
in which Rxe2x80x32 or Rxe2x80x3xe2x80x22 are hydrogen or methyl, preferably hydrogen, those in which Z is a simple bond and those in which R17 is hydroxyl, those in which R17 is hydrogen, ethynyl or propynyl, those in which X is methylene and Y is saturated linear chain of 5 to 10 carbon atoms optionally interrupted by an oxygen atom and those in which X is phenylene and Y is a saturated linear chain of 3 to 10 carbon atoms optionally interrupted by an oxygen atom and those in which X is phenylenoxy and Y is saturated linear chain of 3 to 10 carbon atoms optionally substituted by an oxygen or sulfur atom.
Among the preferred compounds of formula I are those in which either RA and Rxe2x80x2A are both methyl or RA is hydrogen or methyl and Rxe2x80x2A is butyl, or RA is methyl and Rxe2x80x2A is isopropyl, dimethylaminoethyl, benzyl or heptafluorobutyl or RA and Rxe2x80x2A form together a piperazine optionally N-substituted or a pyrrolidine.
Among the specific preferred compounds of formula I are 11 xcex2-N-(2-dimethylaminoethyl)-17 xcex2-hydroxy-N-methyl-3-oxo-xcex44,9-estradien-undecanamide, N-butyl-4-(3,17 xcex2-dihydroxy-xcex41,3,5(10)-estratrien-11 xcex2-yl)-N-methyl-benzene octanamide, 3,17 xcex2-dihydroxy-N-methyl-N-isopropyl-11xcex2-xcex41,3,5(10)-estratrien-undecanamide, N-butyl-3,17xcex2-dihydroxy-N-methyl-19-nor-11xcex2-(17xcex1-xcex41,3,5(10)-pregnatrien-20-yn)-undecanamide, 3,17 xcex2-dihydroxy-N-methyl-N-isopropyl-19-nor-11xcex2-17 xcex1-xcex41,3,5(10)-pregnatrien-20-yn)-undecanamide; [[8-(3,17xcex2-dihydroxy-xcex41,3,5(10)-estratrien-11 xcex2-yl)-octyl]-oxy]-N-methyl-N-isopropyl-acetamide, N-butyl-8-{4-(3,17xcex2-dihydroxy xcex41,3,5(10)-estratrien-11 xcex2-yl)-phenoxy-N-methyl octanamide, N-butyl-[5-[4-(3,17 xcex2-dihydroxy-xcex41,3,5(10)-estratrien-11xcex2-yl)-phenoxy]-pentoxy]-N-methyl acetamide, 2-[(7-[4-(3,17xcex2-dihydroxy-xcex41,3,5(10)-estratrien-11xcex2-yl)-phenyl]-6-heptyl]-oxy]-N-butyl-N-methyl acetamide, 3,17xcex2-dihydroxy-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-xcex41,3,5(10)-estratrien-11 xcex2-yl]-undecanamide and N-[4-(3,17 xcex2-dihydroxy-xcex41,3,5(10)-estratrien-11xcex2-yl)-phenyl-N-butyl-N-methyl octynamide.
Among the preferred compounds of formula IA are those wherein n is 1 or 2, those wherein K is oxygen or sulfur, those wherein Rxe2x80x218 and R18 form xe2x95x90O or R18 is xe2x80x94OH or acyloxy and Rxe2x80x218 is hydrogen or optionally substituted alkyl, alkenyl or alkynyl of up to 8 carbon atoms, those wherein Xxe2x80x2 is methylene, arylene, xe2x80x94CH2Oxe2x80x94, arylenoxy or arylenethio attached to the steroid with a carbon atoms, those wherein Yxe2x80x2 is a simple bond or an optionally unsaturated aliphatic of 1 to 18 carbon atoms optionally interrupted with at least one member of the group consisting of arylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, sulfone or sulfoxide and optionally terminated with arylene, those wherein Zxe2x80x2 is a simple bond when Yxe2x80x2 is a single bond but Xxe2x80x2 is not xe2x80x94CH2xe2x80x94 or xe2x80x94CH2Oxe2x80x94, those wherein RB and Rxe2x80x2B are individually selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms optionally substituted by aryl, alkylamino, dialkylamino, hydroxy, halogen or esterified carboxy or RB and Rxe2x80x2B together with the nitrogen to which they are attached form an optionally unsaturated 5- or 6-member heterocycle optionally containing at least one heteroatom of oxygen, sulfur or nitrogen optionally substituted by alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms or aralkyl of 7 to 10 carbon atoms with the proviso that at least one of RB and Rxe2x80x2B is not hydrogen and at least one of following conditions is met; n=2 or K is sulfur or Xxe2x80x2 is arylenethio attached to the steroid by a carbon atoms or RB and Rxe2x80x2B form with the nitrogen or 5- or 6-member heteroatom substituted by aryl or aralkyl.
Examples of specific compounds of Formula IA are
monobutanedioate of 11xcex2-(4-((7-(butylmethylamino)-carbonyl)-heptyl)-oxy-phenyl)-xcex41,3,5(10)-estratrien-3-ol-17xcex2-yl;
butanedioate of 11xcex2-(4-((7-((butylmethylamino)-carbonyl)-heptyl)-oxy)-phenyl)-xcex41,3,5(10)-estratrien-3-ol-17xcex2-yl and its sodium salt; N-butyl-2-(6-(4-(671,3,5(10)-estratrien-3,17xcex2-diol-11xcex2-yl)-phenoxy)-hexyloxy-N-methyl-acetamide;
N-butyl-8-(4-(xcex41,3,5(10)-estratrien-3,17xcex2-diol-11xcex2-yl)-phenoxy)-N-methyl-2-octynamide;
N-butyl-2-((5-(4-(xcex41,3,5(10)-estratrien-3,17xcex2-diol-11xcex2-yl)-phenyl)-pentyl)-thio)-N-methylacetamide;N-butyl-4-(xcex41,3,5(10)-estratrien-3,17xcex2-diol-11xcex2-yl)-N-methyl-benzenenonamide;
N-butyl-2-((5-(4-xcex41,3,5(10)-estratrien-3,17xcex2-diol-11xcex2-yl)-phenyl)-pentyl)-oxy)-N-methyl-acetamide; and
2-((8-(xcex41,3,5(10)-19-nor-17xcex1-pregnatrien-3,17xcex2-diol-20-yn-11xcex2-yl)-octyl)-oxy)-N-methyl N-(1-methylethyl)-acetamide.
The novel process of the invention for the preparation of the compounds of formula I comprises reacting a compound of the formula 
wherein X, Y, R17 and Rxe2x80x217 have the above definitions with R17 being other than OH either with an oxidizing agent to obtain a product of the formula 
reacting the latter with an agent permitting the activation of the carboxylic function, then with a compound of the formula 
wherein RA and RAxe2x80x2 have the above definitions to obtain the product of formula Ia corresponding to the compound of formula I in which Z is a simple bond and the rings A and B are 
wherein R2 and Rxe2x80x22 are hydrogen or with a compound capable of introducing 
to obtain a compound of formula IIxe2x80x2a which is a compound of Formula I wherein Z is xe2x80x94CH2Oxe2x80x94 and A and B rings have the definition of formula Ia, the compounds of formulae Ia or Ixe2x80x2a optionally being reacted with a reducing agent when R17 and Rxe2x80x217 together form xe2x80x94O, then if appropriate reacting the 17-hydroxylated compound with an acylation agent, or with a saponification agent when R17 is an acyloxy, to obtain a product of formula Ia or Ixe2x80x2a in which R17 has the above meaning, then if desired, reacting one of the products of formula Ia or Ixe2x80x2a, either to obtain an alkylation at position 2, when at least one of R2 and Rxe2x80x22 is hydrogen, or reacts with an aromatization agent of ring A, then to a saponification agent to obtain the products of formula Ib, corresponding to product of formula Ia and the products of formula Ixe2x80x2b corresponding to the products of formula Ixe2x80x2a in which the rings A and B are 
optionally reacting the products of formula Ib and Ibxe2x80x2 to an alkylation or acylation reaction of the 3-hydroxy, then, if desired, either, when R17 and Rxe2x80x217 together form xe2x95x90O to a reducing agent or to a metallic complex of the formula
Mxe2x80x94Rxe2x80x217xe2x80x83xe2x80x83V
wherein M is a metallic ion and Rxe2x80x217 has the above definition other than hydrogen, or when R17 is a hydroxy reacting with an acylation agent selective at position 17, then, if desired, with one of the products of formula I obtained above, or when RA or RAxe2x80x2 is hydrogen with an appropriate alkylation agent.
The compounds of formula I are 19-nor steroids having: either a chain at the 11xcex2-position containing a substituted amide function which compounds are then chosen from among the compounds of formulae Ia and Ib, or a chain at the 11xcex2-position containing a substituted carbamate function which compounds are chosen from among the compounds of formulae Ixe2x80x2a and Ixe2x80x2b.
The compounds of formula Ixe2x80x2a are obtained by reacting a compound of formula II either with an activator of the hydroxyl such as phosgene, then with a primary or secondary amine of formula IV in a neutral solvent such as methylene chloride or tetrahydrofuran in the presence of a base such as potassium carbonate or methylamine, or with an isocyanate of the formula RAxe2x80x94Nxe2x95x90Cxe2x95x90O to obtain a product in which RAxe2x80x2 is hydrogen.
The compounds of formula Ia are obtained by reacting a compound of formula III activated, for example in the form of the mixed anhydride with an agent such as chloroformate, for example, isobutyl chloroformate, in the presence of a base such as a tertiary amine like N-methylmorpholine in an anhydrous solvent such as a chlorinated solvent, i.e., methylene chloride with the amine of formula IV.
The product of formula III is obtained by using an oxidizing agent such as, for example, the mixture CrO3-sulfuric acid in a neutral solvent such as acetone.
In a preferred embodiment of the invention:
The compounds of formula II contain a 11xcex2 chain terminated by an alcohol function selected from the following Table:
as illustrated in the examples hereafter.
The compounds of formula III contain a 11xcex2-chain terminated by a carboxylic acid corresponding to the oxidation product of a chain chosen from among the 11xcex2-chains terminated by one of the alcohol functions cited above.
The compound of formula IV is chosen from the following amines: butylamine, methylbutylamine, dimethylamine, methylisopropylamine, methyldimethylaminoethylamine, methylbenzylamine, pyrrolidine or N-methylpiperazine which are known products.
When the compound of formulae Ia or Ixe2x80x2a has a 17xcex2-ketone, the corresponding 17xcex2-hydroxyl steroid is obtained by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol or triterbutoxylithium aluminium hydride in tetrahydrofuran.
When the compound of formulae Ia or Ixe2x80x2a has a 17xcex2-hydroxy, the corresponding 17-acyloxylated steroid is obtained by the action of an acylation agent, for example an acetylation agent such as acetic anhydride in pyridine, optionally in the presence of 4-dimethylamino-pyridine.
When the compounds of formulae Ia or Ixe2x80x2a have 17xcex2-acyloxy, the corresponding 17xcex2-ol steroid is obtained with a saponification agent such as potassium hydroxide in an alcoholic medium.
When the compounds of formulae Ia or Ixe2x80x2a has one or two hydrogen atoms at position 2 or/and 2xe2x80x2, the corresponding mono or dialkylated steroid at position 2 and 2xe2x80x2 is obtained by the action of an alkylation agent, preferably a methylation agent such as methyl iodide.
The compounds of formulae Ib and Ixe2x80x2b which are steroid derivatives of estradiol having a 11xcex2-chain containing a substituted amide function or a substituted carbamate function are obtained starting with the compounds of formulae Ia and Ixe2x80x2a respectively, by the action of an aromatization agent such as palladium hydroxide on magnesia in methanol or a mixture of acetyl bromide and acetic anhydride at a temperature not exceeding that of ambient followed by a saponification reaction using, for example, potassium hydroxide in methanol, sodium bicarbonate or methanol in the presence of hydrochloric acid.
When the compounds of formulae Ib or Ixe2x80x2b have a 3-hydroxy, the corresponding alkylated steroids is obtained with an alkylation reagent such as alkyl iodide or an alkyl sulfate, for example, methyl sulfate or the corresponding acylated steroid by the action, of a standard acylation reagent such as an acyl halide like acetyl chloride.
When the compounds of formula Ib or Ixe2x80x2b have a 17 ketone, the corresponding 17xcex2-hydroxyl steroids are obtained under the conditions described above for Ia or Ixe2x80x2a, for example by the action of a reducing agent such as sodium borohydride in a neutral solvent such as methanol and the corresponding compound of formulae Ib or Ixe2x80x2b wherein Rxe2x80x217 is alkyl, alkenyl or alkynyl optionally substituted are obtained by using as a complex, for example, a lithium complex according to the process of EP Patent Application 57,115.
When the compounds of formula Ib or Ixe2x80x2b have a 17xcex2-hydroxy, the acyloxyl steroids can be obtained by the action of a selective acylation agent such as acetic anhydride in pyridine.
When RA or RAxe2x80x2 is hydrogen, the corresponding alkylated product may be obtained by the action of an alkyl halide, for example methyl or ethyl iodide, methyl or ethyl bromide in a solvent such as tetrahydrofuran. It is well understood that if Rxe2x80x217 contains an alkyl, alkenyl or alkynyl substituted by a reactive function, this can be provisionally protected by the usual methods.
The novel process of the invention for the preparation of compounds of formula Ixe2x80x2 wherein X is arylene and Y is aliphatic optionally linked to arylene by a double or triple bond and having at least 3 carbon atoms or linked to arylene through an oxygen atom comprises reacting a compound of the formula 
wherein W is either xe2x80x94OH or xe2x80x94Cxe2x89xa1CH, the rings Axe2x80x2 and Bxe2x80x2, Ra17 and Raxe2x80x217 having the same meanings as indicated above for rings A and B, R17 and Rxe2x80x217 and in which the 3- and 17-reactive functions are optionally protected or, when W is xe2x80x94Cxe2x89xa1CH reacted with a halogenation agent of the formula 
wherein Hal is halogen, Z, RA, and RAxe2x80x2 have the above definitions and Yxe2x80x2 is aliphatic Y having 2 carbon atoms missing in the presence of a strong base, and optionally to the action of a deprotection agent to obtain a product of the formula 
which optionally is reacted with a partial or total reducing agent of the triple bond to obtain a product of the formula 
or, in the case where W is xe2x80x94OH to the action of a halogenated derivative of the formula 
in which Hal, Y, Z, RA and RAxe2x80x2 have the above definitions in the presence of an alkaline agent, and optionally reacting with a deprotection agent to obtain a product of the formula 
which optionally, when Y is an unsaturated aliphatic is reacted with a partial or total reducing agent, and the products of formula Ixe2x80x2A, Ixe2x80x2B or Ixe2x80x3A may be subjected to any one of the reactions indicated above for Ia, Iaxe2x80x2, Ib and Ibxe2x80x2.
In a preferred process of the invention, the optional protection groups of the 3- or 17-hydroxyl are selected from the standard groups such as tetrahydropyranyl and tert.-butyl and the halogen of Hal may be bromine, chlorine or iodine. The strong base used is, for example, butyllithium or sodium hydride and the alkaline agent used is an alkali metal hydroxide such as sodium hydroxide. The deblocking of the protected functions may be effected using of a standard hydrolysis agent such as hydrochloric acid and the optional reduction of the triple bond is effected either using hydrogen in the presence of palladium on activated charcoal, barium sulfate and optionally a base such as pyridine or quinoline in the case of a partial reduction. Palladium hydroxide is used alone in the case of a total reduction. In the compound of formula X used initially, W is in the para position.
In a variation of the processes, the products of formula I wherein Z is a simple bond and Y is a linear aliphatic terminated by vinylene before the amide function, a compound of the formula 
corresponding to the product of formula II in which Yxe2x80x3 is the aliphatic chain Y containing 2 carbon atoms missing, is reacted with an oxidation agent to obtain the corresponding aldehyde which is reacted with a phosphorane of the formula 
The products of formula I in which Y is a branched aliphatic chain can be prepared by alkylation of the products of formula I in which Y is a linear aliphatic chain after having, if appropriate, blocked the 3- and/or 17-reactive functions. The alkylation is effected by using an alkyl halide such as methyl iodide in the presence of lithium diisopropylamide. The products of formula III can be prepared by alkaline hydrolysis of the corresponding products containing at 11xcex2 position a xe2x80x94Xxe2x80x94Yxe2x80x94CN chain of ducts obtained starting with products of formula IIxe2x80x2 as defined above in which one protects the hydroxyl functions, then is reacted with a halogenation agent such as an alkali metal halide, for example, sodium iodide and then an alkali metal cyanide such as potassium cyanide.
The process of the invention for the preparation of the compounds of formula IA comprises reacting a compound of the formula 
wherein X, Y, n, Rxe2x80x218 and R18 have the above definition with the proviso if R18 is xe2x80x94OH, it is protected, with an oxidation agent to obtain a compound of the formula 
subjecting the latter to an agent for activating the carboxyl and then with a compound of the formula 
to obtain a compound of the formula 
wherein Z is a simple bond and optionally deprotecting the hydroxy and if desired reacting the compound of formula Vxe2x80x2 with a reducing agent when R18 and Rxe2x80x218 are xe2x95x90O and acylating the 17-hydroxy or with a saponification agent when R18 is acyloxy. The compound of formula Vxe2x80x2 may be subjected to an aromatization agent for the A ring and then with a saponification agent to obtain the compounds of formula IA.
The resulting compounds of formula IA may be subjected to at least one of the following reractions: when R18 and Rxe2x80x218 are xe2x95x90O, they may be reacted with a reducing agent or a metal complex Mxe2x80x94Rxe2x80x218 wherein M is a metal ion and Rxe2x80x218 has the above definition other than hydrogen or when R18 is xe2x80x94OH, they may be selectively acylated in the 17-position or when RB and Rxe2x80x2B are hydrogen, they may be reacted with an appropriate alkylation agent or when Yxe2x80x2 is an unsaturated aliphatic, they may be subjected to a hydrogenation agent to obtain compounds of formula IA where Kxe2x80x2 is oxygen which, if desired, may be reacted with a sulfuration agent to obtain a compound of formula IA where Kxe2x80x2 is xe2x80x94Sxe2x80x94.
The compounds of formula Vxe2x80x2 are obtained by reacting an active compound of formula IVxe2x80x2 in the form of a mixed anhydride by reaction with chloroformate for example isobutyl chloroformate in the presence of a tertiary amine such as N-methyl morpholine in an anhydrous solvent such as methylene chloride with the amine of formula Vxe2x80x2.
The products of formula IIIxe2x80x2 are obtained with an oxidation agent such as a mixture of sulfuric acid and CrO3xe2x80x94 in a neutral solvent such as acetone. In a preferred mode, the compounds of formula IIxe2x80x2 contain a 11 xcex2-group terminated with an alcohol group wherein
As an illustration of some examples, the compounds of formula IIIxe2x80x2 with a 11xcex2-chain terminated with a carboxyl group are obtained by oxidation of a compound with a 11xcex2-chain terminated with a hydroxy group. The compounds of formula IVxe2x80x2 may be an amine such as butylamine, methylbutylamine, methylisopropylamine or benzylpiperidine which are known or methyl heptafluorobutylamine which is prepared infra.
When the compound of formula Vxe2x80x2 was a 17-one group, it may be reacted with a reducing agent such as sodium borohydride in a neutral solvent such as methanol or tritert.-butoxy lithium aluminum hydride in tetrahydrofuran to obtain the corresponding 17xcex2-ol compound. The latter may be reacted with an acylation agent such as acetic anhydride in pyridine in the optional presence of 4-dimethylamino-pyridine to obtain the 17xcex2-acyloxy compound. The latter compounds may be reacted with a saponification agent such as alcoholic potassium hydroxide to obtain the 17xcex2-ol compound.
The compounds of formula IA which are steroid derivatives of estradiol with a 11xcex2-chain containing a substituted amide group are obtained by reacting a compound of formula Vxe2x80x2 with an aromatization agent such as palladium hydroxide on magnesia in methanol or a mixture of acetyl bromide and acetic anhydride at a temperature not greater than room temperature followed by a saponification reaction with for example potassium hydroxide in methanol or sodium bicarbonate or methanol in the presence of hydrochloric acid.
When the compounds of formula IA have a 17-one group, the corresponding 17-ol compound can be prepared by the reducing conditions described for the compounds of formula Vxe2x80x2 such as sodium borohydride in a neutral solvent such as methanol. The compounds of formula IA wherein Rxe2x80x218 is optionally substituted alkyl, alkenyl or alkynyl can be obtained using a complex such as lithium complex as described in EPO Patent No. 57, 115.
When the compounds of formula IA contain a 17-ol group, the 17-acyloxy may be formed by selective acylation with acetic anhydride in pyridine, for example. When RB or Rxe2x80x2B is hydrogen, the corresponding alkyl compound can be obtained by reaction with an alkyl halide such as methyliodide, ethyliodide, methylbromide or ethylbromide in a solvent such as tetrahydrofuran. It is well known that if Rxe2x80x218 is alkyl, alkenyl or alkynyl substituted with a reactive group, that it is possible to protect the same by known methods.
When Yxe2x80x2 is an unsaturated aliphatic, the compounds of formula IA can have the triple bond reduced with hydrogen in the presence of palladium on activated carbon or barium sulfate and optionally with a base such as pyridine or quinoline in the case of a partial reduction. One may use palladium hydroxide alone or chlorotris (triphenylphosphine) rhodium for a total reduction.
The compounds of formula IA wherein Yxe2x80x2 is a branched aliphatic chain may be prepared by alkylation of compounds of formula IA wherein Yxe2x80x2 is a linear aliphatic group while blocking any reactive group in the 3- and 17-positions. The alkylation may be effected with methyliodide in the presence of lithium diisopropylamide, for example.
When Kxe2x80x2 is oxygen, the corresponding compound of formula IA wherein Kxe2x80x2 is sulfur may be obtained by reaction with a sulfurization agent such as [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphenate-2,4-disulfur] or Lawesson reagent after optional blocking of any reactive groups in the 3- and 17-positions.
Another process of the invention for the preparation of compounds of formula IA wherein Yxe2x80x2 is an aliphatic chain optionally containing an arylene attached by a double or triple bond and having at least 3 carbon atoms or an arylene attached by oxygen or sulfur comprises reacing a compound of the formula 
wherein W is selected from the group consisting of xe2x80x94OH, optionally activated mercapto and xe2x80x94Cxe2x95x90CH and n, R18A and Rxe2x80x218A have the above definitions or if R18A is xe2x80x94OH, it is optionally protected, the Axe2x80x2 and Bxe2x80x2 rings are 
and R3 is hydrogen or a xe2x80x94OH protecting group or when W is xe2x80x94Cxe2x89xa1CH with a halogen derivative of the formula 
wherein Hal is halogen, Zxe2x80x2, RB and Rxe2x80x2B have the above definitions and Yxe2x80x3 is the aliphatic chain of Yxe2x80x2 having at least 2 carbon atoms in the presence of a strong base and optionally with a deprotection agent for the 3- and/or 17-positions to obtain a compound of the formula 
optionally subjecting the latter to a partial or total reduction of the triple bond to obtain a compound of the formula 
or when W is xe2x80x94OH or optionally activated mercapto with a halogen derivative of the formula 
wherein Hal, Yxe2x80x2, Zxe2x80x2, RB and Rxe2x80x2B have the above definitions in the presence of an alkaline agent and then with a deprotection agent to obtain a compound of the formula 
wherein Kxe2x80x2 is oxygen or sulfur and the compounds of formulae IXxe2x80x2A, IXxe2x80x2B and IXxe2x80x2C may be reacted as the compounds of formula V above to obtain the compounds of formula IA as individual above.
When W is an activated mercapto, it is formed by reaction with a metal thiolate such as silver thiolate.
In a preferred mode of the process, the 3- and 17-ols are protected by tetrahydropyran or tert.-butyl and Hal is preferably bromine, iodine or chlorine. The strong base is preferably butyllithium or sodium hydride. The optional reduction of the triple bond is effected either with hydrogen in the presence of palladium on activated carbon, barium sulfate and optionally a base such as pyridine or quinoline for a partial reduction or with palladium hydroxide alone or chlorotris (triphenylphosphine) rhodium for a total reduction.
Preferably, the optional activation of mercapto is effected by reaction with a metallic salt such as silver nitrate with the mercapto protected such as a thioether i.e. alkylthio like tert.-butylthio, triphenylmethylthio, isobutoxymethylthio or a derivative of 5- or 6-member ring optionally containing a nitrogen, oxygen or sulfur heteroatom, preferably oxygen. An example of such a protected mercapto is tetrahydropyranylthio.
Preferably, the alkaline agent is an alkali metal hydroxide such as sodium hydroxide and the deblocking of the protected functions is effected with a hydrolysis agent such as hydrochloric acid. The preferred compounds of formula VIIxe2x80x2 have W in the para-position.
The novel hormonal compositions of the invention are comprised of an hormonally effective amount of at least one compound of formula I and IA and an inert pharmaceutical carrier or excipient. The compositions may be in the form of tablets, dragees, capsules, granules, suppositories, pessaries, ointment, creams, gels, microspheres, implants, patches and injectable solutions or suspensions.
Examples of suitable excipients are talc, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants and emulsifiers and preservatives.
The compositions containing compounds of formula I and IA present interesting pharmacological properties. The study of products on the hormonal receptors has brought to the fore that the compounds of formulae Ia and Ib possess glucocoticoid or antiglucocorticoid, progrestomimetic or antiprogestomimetic, androgen or antiandrogen, antimineralocorticoid, estrogen or anti-estrogen activity and the compounds of formulae Ib and Ixe2x80x2b possess particularly a remarkable anti-estrogen activity and anti-proliferative properties as shown by the results of tests given intra.
These properties make the compositions containing compounds of formula Ia and Ixe2x80x2a useful for combatting the side effects of glucocorticoids and permit the combatting of disorders due to a hypersecretion of glucocorticoids and notably the combatting of aging in general and more particularly the combatting of hypertension, atherosclerosis, osteoporosis, diabetes, obesity as well as the depression of immunity and insomnia. These compositions are equally of interest in the treatment of certain hormonal-dependent tumors.
The compositions containing compounds of formulae Ia and Ib which possess antiprogestomimetic properties can be used for the preparation of original contraceptives or as abortion agents and are useful for inducing (menstrual) periods in women and more generally in warm-blooded female animals. The compositions are administered during the periods where progesterone plays an essential physiological role, i.e., during the luteal phase of the cycle, at the moment of nidation (or implanation of the embryo) and during pregnancy. One method of contraception of the invention consists of administering to the women at least one of the products of formula Ia or Ixe2x80x2a over 1 to 5 days, preferably at the end of the cycle. This product is then preferably administered orally or in vagino but it can also be administered parenterally and endonasally.
The compositions containing the compounds of formulae Ia and Ixe2x80x2a possessing anti-progestomimetic properties are also useful against hormone irregularities and, are of interest in the treatment of hormone-dependent tumors. Their actions on hypophysial secretions make the products usable in the menopause and these compositions can be used in the synchronization of estrus in farm animals, particularly cattle and sheep and for controlling the fertility of pets such as dogs or cats. Equally the compositions containing compounds of formulae Ia and Ixe2x80x2a can have progestomimetic properties and can be used in the treatment of amenorrhea, dysmenorrhea and luteal insufficiencies.
The compositions of compounds of formula Ia and Ixe2x80x2a which possess anti-androgenic properties can be used in the treatment of hypertrophia and cancer of the prostate, hyperandrogenia, anemia, hirsutism and acne. Equally they can be used for male contraceptives.
The compositions of compounds of formulae Ia and Iaxe2x80x2 which possess estrogenic properties make them useful in the treatment of disorders linked to a hypofolliculinia for example amenorrhea, dysmenorrhea, repeated miscarriages, premenstrual troubles as well as in the treatment of the menopause and of osteoporosis.
The anti-estrogen and anti-proliferation properties of compositions containing the compounds of formulae Ib and Ibxe2x80x2 and the compounds of formula IA make them useful in the treatment of mammary carcinomas and their metastases and in the treatment of benign tumors of the breast.
Among the preferred compositions of the invention are those containing the compounds of Examples 8, 16, 19, 21, 35, 37, 43, 46, 55, 71, 75, 77, 78, 79, 80, 82, 83, 85, 86 and 89.
The novel method of inducing hormonal activity in warm-blooded animals, including humans, comprises administering to warm-blooded animals an hormonally effective amount of at least one compound of formula I. The compounds may be administered orally, rectally or parenterally and the usual daily dose is 0.013 to 1.33 mg/kg depending upon the method of administration, the condition being treated and the specific compound being administered.
The compounds of formulae II and III are novel intermediates and an object of the invention.
The compounds of formula II may be prepared by reacting a magnesium derivative of a halogenated alcohol of the formula
Halxe2x80x94Xxe2x80x94Yxe2x80x94CH2OR xe2x80x83xe2x80x83VI 
wherein X and Y have the above definitions, Hal is a halogen and R is hydrogen or an alcohol protecting groups such as 
in the presence of a copper salt with a compound of the formula 
wherein K is a ketone protector group such as a cyclic ketal to obtain a compound of the formula 
optionally reacting the latter with a lithium derivative of a compound of the formula
Hxe2x80x94Rxe2x80x217 xe2x80x83xe2x80x83IX 
wherein Rxe2x80x217 has the above definition other than hydrogen or with a reducing agent, then optionally with an acylation agent and then to a dehydration and hydrolysis agent capable of liberating the 3-keto-xcex944 function and the alcohol function to obtain the compound of formula II.
Certain intermediates of formula IIxe2x80x2 and IIIxe2x80x2 are novel, namely those wherein n is 2.
The products of formula VIIxe2x80x2 are known products and their preparation is described, for example, in EP Patent No. 0,057,115. The products of formula Xxe2x80x2 are described notably in European Patent Application No. EP 0,245,170 when n is 1 and in EP application No. 0,116,974 when n is 2, and specific examples of the preparation of products of formula Xxe2x80x2 are described hereinafter in the examples. Examples of the preparation of products of formulae IX and XII are in the experimental part.
Among the preferred new products of formula II of the invention are 17xcex2-acetyloxy-11xcex2-[(8-hydroxy-octyl)-phenyl]-xcex944,9-estradiene-3-one, 11xcex2-(12-hydroxy-dodecyl)-xcex944,9-estradiene-3,17-dione and 11xcex2-(8-hydroxyoctyl)-xcex944,9-estradien-3,17-dione.
Among the preferred products of formula III of the invention are 17xcex2-acetyloxy-3-oxo-11xcex2-xcex944,9-estradiene-undecanoic acid, 3,17-dioxo-11xcex2-xcex944,9-estradiene undecanoic acid and 17xcex2-hydroxy-3-oxo-17xcex1-(1-propynyl)-11xcex2-xcex944,9-estradiene undecanoic acid.
The following products are products able to be obtained within the scope of the present invention:
The products of formula VIIxe2x80x2 wherein n is 1 and W is other then mercapto are described in European Patent application No. 0,245,170 and the products where n is 2 and W is other than mercapto may be prepared by the process for the preparation of compounds of formula XIIxe2x80x2 where n is 2.
The compounds of formula VIIxe2x80x2 where W is optionally activated mercapto are novel and may be prepared by reaction of a magnesium compound containing a mercapto with a compound of formula VIIxe2x80x2. Specific examples are described infra.
In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.
Step A: (5xcex1,11xcex2)-3-(1,2-ethanediyl cyclic acetal) of 5xcex1-hydroxy-11xcex2-[4-[2-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-methyl]-phenyl]-xcex949-estrene-3,17-dione
Preparation of the Magnesium Reagent:
To a suspension of 1.4 g of magnesium turnings in 20 ml of tetrahydrofuran, 19.9 g of the brominated derivative obtained from preparation 9 in solution in 60 ml of tetrahydrofuran were added dropwise followed by stirring for 1 hour at 50xc2x0 C. to obtain a solution with a titre=0.85 mole/liter.
Condensation:
For 10 minutes at ambient temperature, a solution of 4.5 g of 3-(1,2-ethanediyl cyclic acetal) of 5xcex1,10xcex1-epoxy-xcex949,11-estrene-3,17-dione [EP 0,057,115 (Example 7)] in 45 ml of tetrahydrofuran and 0.4 g of cupric chloride was stirred and over a period of 20 minutes, 50 ml of the magnesium reagent above were added without exceeding 27xc2x0 C. After 90 minutes of stirring, the mixture was poured into an ice-cooled solution of ammonium chloride. The aqueous phase was extracted once with ethyl acetate and 3 times with methylene chloride to obtain 15.423 g of a product which was chromatographed over silica (eluant:cyclohexane=ethyl acetate (7-3) to obtain 6.29 g of the desired product.
Step B: 3-(1,2-ethanediyl cyclic acetal) of 5xcex1,17xcex2-dihydroxy-11xcex2-[4-2-[[(1-dimethylethyl)-dimethylsilyl]-oxy]-methyl]-phenyl]-xcex949-estren-3-one
To a solution of 6.15 g of the product of Step A in 100 ml of methanol, 6 g of sodium boron hydride were added over 13 minutes and the mixture was stirred for two hours and poured into 500 ml of water and extracted with methylene chloride. The organic phase was evaporated to dryness to obtain 6.17 g of the desired product which was used as such in the following step.
Step C: 17xcex2-acetyloxy-11xcex2-[4-(2-methyl)-phenyl]-xcex944,9-estradien-3-one
a) Acetylation
To a solution of 6.1 g of the product of Step B in 52 ml of pyridine and 1.15 g of 4-dimethylamino-pyridine, 5.2 ml of acetic anhydride were added and the mixture was stirred for 20 minutes and poured into 200 ml of an ice-cooled solution of sodium bicarbonate. The mixture was stirred for 10 minutes and extracted with methylene chloride. The organic phase was evaporated to dryness to obtain 6.828 g of the expected amorphous product.
b) Hydrolysis
The said product was taken up in 40 ml of 2N hydrochloric acid and 50 ml of ethanol and was stirred for 1 hour at ambient temperature and concentrated to half-volume under reduced pressure. The mixture was diluted with 100 ml of water, and extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica (eluant:cyclohexane=ethyl acetate (1-1) to obtain 3.39 g of the desired product.
Step A: 3-(1,2-ethanediyl cyclic acetal) of 11xcex2-(5-hydroxy-pentyl)-xcex949-estrene-5xcex1-ol-3,17-dione
Preparation of the Magnesium Reagent of 1-chloro-5-pentanol
To a solution of 24.6 ml of 1-chloro-5-propanol in 246 ml of tetrahydrofuran, 300 ml of a 0.67 M/liter solution of the magnesium reagent of 2-chloropropane in tetrahydrofuran was added over 20 minutes at xe2x88x9220xc2x0 C. and the mixture was stirred for 20 minutes at xe2x88x9220xc2x0 C. 7.3 g of the magnesium reagent in shavings were added followed by 0.5 ml of dibromoethane. The mixture was refluxed for 1 hour, 0.5 ml of dibromoethane were added and then reflux was continued for two hours. The mixture returned to ambient temperature to obtain the solution of the desired magnesium reagent titering 0.18 M/liter.
Condensation:
To a mixture of 12 g of the 5,10 epoxy compound of EP 0,057,115 (Example 7) and 600 mg of cuprous chloride in 150 ml of tetrahydrofuran, 570 ml of the magnesium reagent were added dropwise at xe2x88x9250xc2x0 C. and the mixture was stirred for a further 30 minutes and poured into a mixture of 250 ml of a saturated solution of ammonium chloride and 250 g of ice. The mixture was extracted with chloroform and the organic phase was washed with a saturated solution of sodium chloride, dried and evaporated to to dryness under reduced pressure. The 35 g of the residue were chromatographed over silica (eluant:methylene chloridexe2x88x92acetone) (85-15)) to obtain 13.5 g of the desired product.
Step B: 11xcex2(5-hydroxy pentyl)-xcex944,9-estadiene-3,17-dione
For 90 minutes, a mixture of 5 g of the product of Step A, 110 ml of ethanol and 28 ml of 2N hydrochloric acid was stirred and the mixture was made alkaline to pH of about 9 with concentrated ammonia. The mixture was washed with water, and a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 4.8 g of residue were chromatographed over silica (eluant:methylene chloridexe2x88x92acetone (85-15)) to obtain 3.97 g of the expected product.
Step C: 3,17-dioxo-11xcex2-xcex944,9-estradiene-pentanoic acid
To a solution of 2.9 g of the product of Step B in 140 ml of acetone cooled down to xe2x88x924xc2x0 C., 1 ml of Heilbron-Jones reagent were added over 25 minutes at 0xc2x0 to xe2x88x924xc2x0 C. and the mixture was stirred for a further 5 minutes at 0xc2x0 C. The excess reagent was destroyed by the addition of 2.5 ml of methanol and a solution of 22 g of barium carbonate in 220 ml of water was added. The mixture was stirred for 1 hour at ambient temperature and filtered to remove the mineral salts which were washed 5 times with 200 ml of acetone. The acetone was evaporated and the aqueous phase was extracted 4 times with 200 ml of methylene chloride. The organic phase was washed with water, and sodium chloride in saturated solution and evaporated to dryness under reduced pressure to obtain 3.4 g of the desired product used as such in the following step.
Step A: 3-(1,2-ethanediyl cyclic acetal) of 11xcex2-(7-hydroxy heptyl)-xcex949-estrene-5xcex1-ol-3,17-dione
Using the procedure of Step A of Preparation 2, 14.4 g of 1-chloro-7-heptanol [obtained in Preparation 10 starting from 13.9 g of the 5xcex1,10xcex1-epoxide of EP 0,057,115 Example 7] yield. 26.9 g of crude product which was chromatographed over silica (eluant:methylene chloride-acetone-triethylamine (85-15-0.4)) to obtain 9 g of the desired product. The latter was chromatographed once more (eluant:ethyl acetate-cyclohexane-triethylamine (60-40-0.4)) to obtain 8.17 g of the desired product.
Step B: 11xcex2-(7-hydroxyheptyl)-xcex944,9-estradiene-3,17-dione
Using the procedure of Step B of Preparation 2, 2.5 g of the product of Step A were reacted and after chromatography over silica (eluant:cyclohexane-diethyl acetate (1-1)), 1.935 g of the desired product were obtained.
Step C: 3,17-dioxo-11xcex2-xcex944,9-estradiene heptanoic acid
Using the procedure of Step C of Preparation 2, 3.2 g of the product of Step B were reacted to obtain 3.04 g of the desired product which was used as such in the following step.
Step A: 3-(1,2-ethanediyl cyclic acetal) of 11xcex2-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-ocytl]-phenyl]-xcex949-estrene-5xcex1-ol-3,17-dione
Using the procedure of Step A of Preparation 1, 3.171 g of the epoxide of EP 0,057,115 (Example 7) and 9.9 g of dimethyl tert.-butyl silyl octanyloxy bromobenzene (of Preparation 11) were reacted to obtain after chromatography over silica (eluant:cuyclohexane-ethyl-acetate (6-4)), 4.127 g of the desired product.
Step B: 3-(1,2-ethanediyl cyclic acetal) of 11xcex2-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-octyl]-phenyl]-xcex949-estren-5xcex1,17xcex2-diol-3-one
Using the procedure of Step B of preparation 1, 2.62 g of the product of Step A were reacted to obtain 2.6 g of the desired product for use as is in the following step.
Step C: 3-(1,2-ethanediyl cyclic acetal) of 17xcex2-acetyloxy-11xcex2-[4-[8-[[(1,1-dimethyl ethyl)-dimethylsilyl]-oxy]-octyl]-phenyl]-xcex949-estren-5xcex1-ol-3-one
Using the procedure of (a) Step C of preparation 1, the product of Step B was reacted to obtain after chromatography on silica (eluant:cyclohexane-ethyl acetate (6-4)), 2.58 g of the desired product.
Step D: 17xcex2-acetyloxy-11xcex2-[4-(8-hydroxy-octyl)-phenyl-xcex944,9-estradien-3-one
Using the procedure of (b) Step C of preparation 1, the product of Step C was reacted to obtained after chromatography on silica (eluant:cyclohexane-ethyl acetate (5-5), 1.2 g of the desired product.
Step A: 3-(1,2-ethanediyl cyclic acetal) of 11xcex2-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-xcex949-esterene-5-ol-3,17-dione
Using the procedure of Step A of preparation 1, 17.5 g of the epoxide of EP 0,057,115 (Example 7) and 500 ml of a 0.32 M suspension in tetrahydrofuran of 11-(dimethyl-tert-.butylsilyloxy)-undecyl magnesium bromide (prepared by ICI Patent No. 85-100658) were reacted to obtain after chromatography on silica (eluant:cyclohexane-ethyl acetate (95-5 then 5-5)), 15.3 g of the desired product.
Step B: (1,2-ethanediyl cyclic acetal) of 11xcex2-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-xcex949-estren-5xcex1,17xcex2-diol-3-one
Using the procedure of Step B of preparation 1, 15.2 g of the product of Step A were reacted to obtain 14.863 g of the desired product, which was used as is for the following step.
Step C: (1,2-ethanediyl cyclic acetal) of 17xcex2-acetyloxy-11xcex2-[11-[[dimethyl-(1,1-dimethyl ethyl)-silyl]-oxy]-undecyl]-xcex949-estren-5xcex1-ol-3-one
A mixture of 13.335 g of the product of Step B, 53 ml of pyridine and 26 ml of acetic anhydride was stirred for 4 hours 30 minutes at ambient temperature and was then cooled and neutralized by adding, over 45 minutes, sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with water, dried and evaporated to dryness under vacuum to obtain 15 g of the desired product which was used as is for the following step.
Step D: 17xcex2-acetoxy-11xcex2-(11-hydroxy-undecyl)-xcex944,9-estradien-3-one
A mixture of 15 g of the product of Step C, 300 ml of methanol and 75 ml of 2N hydrochloric acid was stirred for 2 hours 45 minutes and then 20 ml of concentrated ammonia were added and the methanol was evaporated under vacuum. The mixture was extracted with ethyl acetate and the organic phase was washed with water saturated with sodium chloride, dried and evaporated to dryness under vacuum to obtain 12.75 g of product which was chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 8.37 g of the desired product.
Step E: 17xcex2-acetoxyloxy-3-oxo-11xcex2-xcex944,9-estradiene-undecanoic acid
Using the procedure of Step C of preparation 1, 8.37 g of the product of Step D were reacted to obtain after chromatography on silica (eluant:cyclohexane-ethyl acetate (5-5)), 6.67 g of the desired product.
Step A: 11xcex2-(11-hydroxy undecyl)-xcex944,9-estradiene-3,17-dione
A mixture of 1 g of the product of Step A of preparation 5, 20 ml of methanol and 5 ml of 2N hydrochloric acid was stirred for 75 minutes at ambient temperature and the mixture was made alkaline to pH approx. 9 with concentrated ammonia, then was evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed with a saturated sodium chloride solution, dried and concentrated to dryness under reduced pressure. The dry extract was chromatographed on silica (eluant:cyclohexane-ethyl acetate (6-4)) to obtain 670 mg of the desired product.
Step B: 3,17-dioxo-11xcex2-xcex944,9-estradiene undecanoic acid
Using the procedure of Step C of preparation 2, 10.4 g of the product of Step A were reacted to obtain 12.4 g of the desired product which was used as is for the following step.
Step A: 3,3-dimethyl ketal of 5xcex1,10xcex1-epoxy-xcex949,11-estradiene-3,17-dione
To a solution of 5 kg of 3,3-dimethyl ketal-xcex944,9-estradien-17-one (French Patent No. 1,514,086) in 25 liters of methylene chloride and 25 ml of pyridine, 430 g of hexachloroacetone and 1.3 liters of 200 volume hydrogen peroxide were added and the mixture was stirred for 24 hours at 16 to 18xc2x0 C. and poured into a mixture of 1,400 kg of sodium thiosulfate and 50 liters of demineralized water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure to obtain 7.29 kg of the desired product which was used as is for the following step.
Step B: 3,3-dimethyl ketal of 11xcex2-(11-dimethyl tert-butyl silyloxy undecyl)-xcex949-estrene-5xcex2-ol-3,17-dione
To 600 ml of the magnesium derivative of bromo undecyloxy dimethyl tert-butyl silane (ICI Patent No. 85-100658) in 50 ml of tetrahydrofuran cooled to 0xc2x0 C., there was added 1.58 g of cuprous chloride and the mixture was stirred for 30 minutes and cooled to xe2x88x9230xc2x0 C. A solution of 18.17 g of the product of Step A in solution in 87 ml of tetrahydrofuran was added and the mixture was stirred for 3 hours and 30 minutes at ambient temperature, then poured into a solution of ammonium chloride at 0xc2x0 C. The mixture was stirred for 10 minutes and extracted with ethyl acetate followed by methylene chloride. The organic phases were washed with saturated aqueous sodium chloride, dried and evaporated to dryness under reduced pressure. The 123 g of residue was chromatographed on silica (eluant:methylene chloride-ethyl acetate (9-1) with 1% of triethylamine) to obtain 5.19 g of the desired product used as is in the following step.
Step C: 11xcex2-(11-hydroxy undecyl)-17xcex1-(1-propynyl)-xcex944,9-estradiene-17xcex2-ol-3-one
84 ml of butyl lithium in hexane (1.6 mol/liter) were cooled to xe2x88x9270xc2x0 C. and slowly 84 ml of tetahydrofuran were added. Methyl acetylene was bubbled therethrough while maintaining the temperature at xe2x88x9250xc2x0 C. and after 10 minutes, the temperature fell to xe2x88x9270xc2x0 C. The bubbling in was stopped and the mixture was stirred for 30 minutes at xe2x88x9270xc2x0 C. 4.18 g of the product of Step B in solution in 80 ml of tetrahydrofuran were added and the temperature returned to ambient temperature. The mixture was stirred for 1 hour under these conditions and poured into a solution of ammonium chloride at 0xc2x0 C. The mixture was extracted with ethyl acetate and then methylene chloride and the organic phases were washed, dried and evaporated to dryness under reduced pressure. The 6 g of residue were redissolved in 50 ml of ethanol and 10 ml of 2N hydrochloric acid and the mixture was stirred for 1 hour at ambient temperature and diluted with 100 ml of water. The mixture was extracted with chloroform and the organic phase was evaporated to dryness. The 4.9 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5) to obtain 2.25 g of the desired product.
Step D: 17xcex2-acetyloxy-11xcex2-(11-hydroxy undecyl)-17xcex1-(1-propynyl)-xcex944,9-estradien-3-one
a) Diacetylation.
A solution of 5.07 g of the product of Step C of Example 9 in 48 ml of pyridine, 1 g of 4-dimethylamino-pyridine and 17.6 ml of acetic anhydride was stirred for 18 hours at 20xc2x0 C. and then 200 ml of ice were added all at once. The mixture was neutralized with a saturated sodium bicarbonate solution and stirred for 30 minutes followed by extraction with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the 8 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 2.83 g of the desired product.
b) Mono-saponification.
A solution of 2.8 g of the diacetylated product in 28 ml of methanol with 0.7 g of potassium bicarbonate was heated to 70xc2x0 C. for 90 minutes and then 100 ml of iced water were added. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness. The 2.6 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 1.18 g of the desired product used as is for the following step.
Step E: 17xcex2-acetyloxy-3-acetyloxy-3-oxo-17xcex1-(1-propynyl)-11xcex2-xcex944,9-estradiene undecanoic acid
To a solution of 460 mg of the product of Step A in 24 ml of acetone, 0.8 ml of a solution prepared from 57 ml of concentrated sulfuric acid, 67 g of chromic oxide and sufficient water to make to 250 ml were added over 1 hour at 0xc2x0 C.
8 drops of methanol, 28 ml of water and 8 g of barium carbonate were added to the reaction solution at 0xc2x0 C. and the mixture was stirred for 1 hour at 0xc2x0 C. and filtered to remove the insoluble material. The filtrate was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure and the 384 mg of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (5-5)) to obtain 198 mg of the desired product.
Step F: 17xcex2-hydroxy-3-oxo-17xcex1-(1-propynyl)-11xcex2-xcex944,9-estradiene undecanoic acid
A solution of 722 mg of the product of Step B in 8 ml of a 1 M solution of methanolic potassium hydroxide was stirred at room temperature for one hour and 10 g of ice, then 10 ml of normal hydrochloric acid were added all at once. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure to obtain 593 mg of the desired product used as is for the following step.
Step A: 3-(1,2-ethanediyl cyclic acetal) of 11xcex2-[12-[[(1,1-dimethylethyl)-dimethylsilyl]-oxy]-dodecyl]-xcex949-estrene-5xcex1-ol-3,17-dione
Using the procedure of Step A of preparation 1, 2.97 g of the epoxide of European Patent No. 0,057,115 (Example 7) and 12 g of dodecanoxy dimethyl tert-butyl silane magnesium bromide (preparation 13) were reacted to obtain, after chromatography on silica (eluant:cyclohexane-ethyl acetate (6-4)), 5.24 g of the desired product.
Step B: 11xcex2-(12-hydroxy-dodecyl-xcex944,9-estradiene-3,17-dione
Using the procedure of Step A of Preparation 6, 5.2 g of the product of Step A were reacted and after chromatography on silica (eluant:cyclohexane-ethyl acetate (6-4)), 2.78 g of the desired product were obtained.
To a solution of 15 g of 4-bromophenethyl alcohol in 60 ml of tetrahydrofuran at 0xc2x0 C. to 5xc2x0 C., 10.6 g of imidazole were added followed by addition over 30 minutes of a solution of of 14.33 g of dimethyl tert-butyl chlorosilane in 20 ml of tetrahydrofuran at 0xc2x0xc2x12xc2x0 C. The mixture was diluted with 40 ml of tetrahydrofuran and was then stirred for 2 hours at ambient temperature and filtered to remove the insoluble material. The filtrate was evaporated to dryness under reduced pressure and the 32.89 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (95-5)), to obtain 24 g of the desired product.
IR Spectrum: (CHCl3) Absence of OH Presence of 
A mixture of 44 g of heptane diol, 400 ml of concentrated hydrochloric acid, 150 ml of toluene and 50 ml of water was stirred for two and half hours at reflux. The toluene fraction was removed and 200 ml of toluene were added to the aqueous fraction and the mixture was heated for five hours at 85xc2x0 C. to 90xc2x0 C. The toluene was removed and 200 ml of toluene and 100 ml of concentrated hydrochloric acid were added to the aqueous phase. The mixture was heated for five hours, then cooled and the organic fraction was combined with the two preceding toluene fractions. The toluene fraction was washed with water, dried and evaporated to dryness under reduced pressure, then distilled at 70xc2x0 C. under 0.5 mm of mercury to obtain 37 g of the desired product.
Step A: Chlorohexyloxy dimethyl tert-butyl silyl
To a mixture of 40.93 g of 1-chlorohexanol, 42.9 g of imidazole and 102 ml of tetrahydrofuran, a solution of 56.07 g of dimethyl tert-butyl silyl chloride in 114 ml of tetrahydrofuran was added at 15 to 18xc2x0 C. and the mixture was stirred for 15 hours at ambient temperature and then centrifuged to remove the precipitate. Chromatography on silica (eluant:cyclohexane-ethyl acetate (95-5)) obtained 74.28 g of the desired product.
Step B: Dimethyl tert-butyl silyl octyloxy bromobenzene
a) Chlorohexyloxy dimethyl tert-butyl silyl magnesium.
A solution of 74.82 g of the product of Step A in 300 ml of tetrahydrofuran was added to a suspension of 0.871 g of magnesium and 271 ml of tetrahydrofuran and the mixture was refluxed for 4 hours and cooled to obtain the desired magnesium derivative with a titer approximately 0.375 mol/liter
50 g of iodoethyl benzene (Preparation 12) in 500 ml of tetrahydrofuran were added at xe2x88x9270xc2x0 C. over 15 minutes to 640 ml of the magnesium derivative solution and the mixture was stirred while allowing a return to ambient temperature and the stirring was continued for 15 hours. 500 ml of water saturated with ammonium chloride were added and the mixture was stirred for 15 minutes. The decanted organic phase was washed, dried and evaporated to dryness and the 101.3 g of residue were chromatographed on silica (eluant:cyclohexane) obtain 39.5 g of the desired product.
Step A: 1-p-bromophenethyl Alcohol
To a solution of 95.2 g of 4-bromophenyl acetic acid in 950 ml of tetrahydrofuran, 49 ml of 10 M borane-dimethyl sulfide complex were added over 35 minutes at 15 to 20xc2x0 C. and the mixture was refluxed over 20 minutes and maintained for 10 minutes, then cooled. 50 ml of water were added and the mixture was extracted with ethyl acetate and evaporated to dryness under reduced pressure. The 102 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (6-4)) to obtain the desired product.
Step B: 1-p-bromophenethyl p-toluene sulfonate
To a solution of 41 g of the alcohol of Step A in 102 ml of pyridine, 77.72 g of tosyl chloride were added over 35 minutes at 5xc2x0 C.xc2x11xc2x0 C. and the mixture was stirred for another 30 minutes at 5xc2x0 C., then allowed to return to ambient temperature. 500 ml of of saturated sodium bicarbonate solution were added and the mixture was extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain 71.4 g of the desired product melting at 92xc2x0 C.
Step C: 1-p-bromophenethyl iodide
To a solution of 71.4 g of the p-toluene sulfonate of Step B in 1,400 ml of acetone, 45.12 g of sodium iodide were added and the mixture was heated to a slight reflux which was maintained for 2 hours, then cooled. The mixture was centrifuged to remove the precipitate which was washed with acetone. The filtrate was evaporated to dryness under reduced pressure and the 80.5 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (8-2)) to obtain 60.54 g of the desired product melting approximately at 40xc2x0 C.
To a solution of 10 g of 12-bromo-1-decanol in 40 ml of tetrahydrofuran, 5.48 g of imidazole were added and over 10 minutes a solution of 7.058 g of dimethyl tert-butyl chlorosilane in 10 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble material was filtered off. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed on silica (eluant:cyclohexane-ethyl acetate (95-5)) to obtain 13.57 g of the desired product usable as is for Step A of Example 15.
100 ml of anhydrous ether and 100 ml of anhydrous tetrahydrofuran was cooled down to 0xc2x0 C. and the methyl amine was bubbled through for 10 minutes. 44.98 g of heptafluorobutyric anhydride were introduced over half an hour, while maintaining a weak bubbling through of methyl amine. The mixture was stirred while allowing the temperature to return to ambient and was then distilled to a small volume under reduced pressure. The mixture was taken up in 200 ml of anhydrous tetrahydrofuran and 30 ml of dioborane-dimethyl sulfide complex were introduced slowly. The mixture was refluxed for 16 hours, cooled down to ambient temperature and then 200 ml of methanol were introduced slowly. Then, gaseous hydrochloric acid was bubbled through for 15 minutes and the reaction medium was refluxed for one hour. The solvents were distilled off under reduced pressure and the residue was taken up in 200 ml of methanol. Gaseous hydrochloric acid was again bubbled through for 10 minutes, followed by refluxing for 2 hours. The solvent was distilled off and the residue was stirred in 100 ml of ice-cooled 6N hydrochloric acid for 10 minutes. After separating, washing with 2N hydrochloric acid and drying, 22.699 g of the expected product were obtained. The hydrochloride was purified by crystallization from 140 ml of ethanol. Then, 140 ml of ether were added and the mixture was stirred for half an hour, followed by separating, washing with ether and drying under reduced pressure to obtain 21.7 g of the desired product (subliming at about 200xc2x0 C.).
13.8 ml of triethylamine and then 200 mg of 4-dimethyl amino-pyridine were added under a nitrogen atmosphere to a solution of 10.2 g of 5-chloropentanol in 80 ml of methylene chloride. The mixture was cooled down to xe2x88x9210xc2x0 C. and 13.75 g of tertbutyl chloro dimethyl-silane were added. The mixture was stirred for 15 minutes at xe2x88x9210xc2x0 C. then left to reheat to ambient temperature and diluted with a saturated solution of sodium bicarbonate. The oily crude derivative was separated out and chromatographed on silica (eluant:cyclohexane-ethyl acetate 95-5) to obtain 18 g of the expected product.
Step A: 3-[[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-propanol
9.46 g of sodium hydride at 50% in oil were introduced into a spherical flask placed under an argon atmosphere and the oil was eliminated by washing with hexane. 380 ml of tetrahydrofuran and 15 g of 1,3-propanediol were added and the mixture was stirred for one hour at ambient temperature. After cooling the mixture to +5xc2x0 C., 29.7 g of terbutyl-chlorodimethyl silane were added and the mixture was stirred for one hour at ambient temperature and then poured into 3.5 liters of ethyl ether. It was washed with 1 liter of a 10% aqueous solution of potassium carbonate, then with 1 liter of a saturated aqueous solution of sodium chloride, then dried over sodium sulfate and evaporated to dryness under reduced pressure. The 3.5 g of residue were chromatogrpahed on silica (eluant:ethyl acetate-cyclohexane 4-6) to obtain 30.6 g of the expected product.
Step B: [(3-bromopropyl)-oxy]-dimethyl-(1,1-dimethyl-ethyl)-silane
5.44 g of tetrabromomethane and 4.30 g of triphenyl-phosphine were added to a solution of 2.5 g of the product of Step A in 27 ml of methylene chloride cooled down to xe2x88x9225xc2x0 C. The reaction solution was stirred for 90 minutes at 0xc2x0 C. and then was chromatographed on silica (eluant:ethyl acetate-cyclohexane 1-9) to obtain 2.885 g of the expected product.
150 g of 97% bromo iodo benzene, 500 ml of anhydrous dimethylformamide, 100 ml of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 of copper iodide and 2.22 g of bis-(triphenyl-phosphine)-palladium (II) dichloride were mixed together and stirred for 2 hours. Then, 500 ml of ice-cooled water were added and extraction was carried out 3 times with 500 ml of ethyl acetate. The organic phase was washed with salt water, then dried over sodium sulfate. The solvents were evaporated under reduced pressure to obtain 136.54 g of a brown oil. Purification was carried out by distillation under reduced pressure to obtain 106.97 g of the expected product with a boiling point of 75xc2x0 C. to 82xc2x0 C. under 0.2 mbar and a melting point of 62xc2x0 C.
IR Spectrum: (CHCl3) absence of Cxe2x95x90CH Cxe2x89xa1C 2160 cmxe2x88x921 
1.55 g of imidazole were added to a solution fo 3.97 g of 8-bromo octanol in 19 ml of dimethylformamide, and over 10 minutes, 3.32 g of terbutyl chloro dimethyl silane in solution in 4.7 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica (eluant:cyclohexane-toluene 8-2) to obtain 5.4 g of the expected product.
STEP A: cyclic 3-(1,2-ethanediyl)-acetal of 11xcex2-(4-hydroxyphenyl)-xcex49-estren-5xcex1-ol-3,17-dione
a) Preparation of the magnesium compound
50 g of trimethylsilyloxy 4-bromo benzene in 100 ml of tetrahydrofuran were added dropwise at reflux to a suspension of 7.1 g of magnesium turnings in 14.5 ml of tetrahydrofuran. After stiring for 30 minutes at reflux, a solution of about 0.95 M of magnesium compound was obtained.
b) Condensation
10 g of cyclic 3-(1,2-ethanediyl) acetal of 5,10 xcex1-epoxy-xcex49,11-estradien-3,17 dione [obtained by EP 0,057,115 (Example 7)] in solution in 200 ml of tetrahydrofuran and 0.45 g of copper chloride were stirred for 10 minutes at ambient temperature. 110 ml of the magnesium compound solution were added over 20 minutes, without exceeding 27xc2x0 C. After 90 minutes of stirring, the mixture was poured into 1300 ml of a saturated ice-cooled solution of ammonium chloride. The aqueous phase was extracted 3 times with ethyl acetate, washed with a saturated solution of dehydrated sodium chloride and evaporated to dryness under reduced pressure to obtain 34.9 g of crude product.
c) Desilylation
The crude product was dissolved in 150 ml of tetrahydrofuran and 130 ml of a 1M solution of tetrabutylammonium fluoride were added. The mixture was stirred for 15 minutes at ambient temperature and then poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to dryness under reduced pressure to obtain 26.9 g of crude product which was made into a paste at 40xc2x0 C. over 30 minutes in 100 ml of an ethyl acetatexe2x80x94methylene chloride mixture (1-1). The insoluble part was filtered off and 5.77 g of the desired product were obtained. The mother liquors were chromatographed on silica (eluant: ethyl acetatexe2x80x94methylene chloride (1-1) and an additional 5.7 g of desired product were collected. The combined two batches of product (11.47 g) were crystallized from ethanol to obtain 8 g of expected product melting at 225xc2x0 C.
STEP B: 11 xcex2-(4-hydroxyphenyl)-xcex44,9-estradien-3,17-dione
5 g of the product of Step A, 110 ml of ethanol and 28 ml of 2N hydrochloric acid were stirred for 90 minutes and the mixture was alkalized to a pH of about 9 with concentrated liquid ammonia and evaporated to dryness. The residue was taken up in ethyl acetate, washed with water and with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The 4.8 g of residue were chromatographed on silica (eluant: methylene chloridexe2x80x94ethyl acetate 7-3) to obtain 3.97 g of the desired product.
STEP A: bromo N-butyl N-methyl acetamide
26 g of butylmethylamine in solution in 120 ml of ether were added to a solution, cooled down to xe2x88x9220xc2x0 C., of 11.9 ml of bromo-acetyl bromide in 180 ml of ether. The temperature was returned to 20xc2x0 C. and the mixture was stirred for 30 minutes, diluted with water and extracted with ether. The extracts were evaporated to dryness under reduced pressure. The 27.4 g of residue were distilled under reduced pressure (0.05 mbar) at 79xc2x0 C. to 83xc2x0 C. to obtain 19.36 g of the desired product.
STEP B: 5-[[(dimethyl-1,1-dimethylethyl)-silyl]-oxy]-pentanol
19.14 g of tertbutyl chlorodimethylsilane were added while cooling to a solution of 10 g of 4-pentanol, 200 ml of methylene chloride, 19.5 ml of triethylamine and 566 mg of 4-dimethylamino-pyridine. The mixture was stirred for one hour at ambient temperature, diluted with water and the organic phase was decanted, washed, dried and evaporated to dryness under vacuum. The 42 g of residue were chromatographed on silica (eluant: essence Gxe2x80x94ethyl acetate 95-5) to obtain 23.3 g of silyloxy pentene which was dissolved in 250 ml of tetrahydrofuran. 6 ml of borane-methylsulfide complex were added at 20xc2x0 C. and the mixture was stirred for 30 minutes at 20xc2x0 C. to 25xc2x0 C., then for 30 minutes at 35xc2x0 C. 18 ml of sodium hydroxide, then 18 ml of hydrogen peroxide were added at +10xc2x0 C. The mixture was stirred for 30 minutes and was diluted with water and extracted with ethyl acetate. The extracts were washed with a 10% solution of sodium thiosulfate, dried and concentrated to dryness under reduced pressure. The 25.85 g of residue were chromatographed on silica (eluant: cyclohexanexe2x80x94ethyl acetate 8-2) to obtain 22.7 g of product which was distilled under reduced pressure (0.06 mbar) to obtain 18.7 g of the desired compound with a boiling point of 73xc2x0 C. to 75xc2x0 C. at 0.06 mbar.
STEP C: N-butyl-[(5-hydroxypentyl)-oxy]-N-methyl acetamide
2.16 g of sodium hydride at 50% in oil were added to a solution of 8 g of the alcohol of Step B in 40 ml of tetrahydrofuran and the mixture was stirred for 30 minutes at ambient temperature. A solution of 9.5 g of the brominated product of Step A in 13 ml of tetrahydrofuran were added dropwise over 15 minutes. After stirring for 16 hours at ambient temperature, a saturated aqueous solution of ammonium chloride was added. Extraction was carried out with ethyl acetate and the extracts were washed, dried and evaporated to dryness under vacuum to obtain 14.8 g of intermediate N-butyl-[[5-[[dimethyl-(1,1-dimethylethyl)-silyl]-oxy]-pentyl]-oxy]-N-methyl acetamide which was dissolved in 83 ml of tetrahydrofuran and 46 ml of a 1M solution of tetrabutyl ammonium fluoride. The mixture was stirred for 2 hours at ambient temperature and then poured into water and extracted with ethyl acetate. The extract was evaporated to dryness under reduced pressure. The 13.6 g of residue were chromatographed on silica (eluant: methylene chloridexe2x80x94isopropanol 94-6) to obtain 7.28 g of the desired compound.
STEP D: [(5-bromopentyl)-oxy]-N-butyl-N-methyl acetamide
13 g of tetrabromo-methane and 10.3 g of triphenyl-phosphine were added at xe2x88x9210xc2x0 C. to a solution of 7.2 g of the product of Step C in 73 ml of methylene chloride. The reaction medium was stirred for one hour at 0xc2x0 C. and chromatographed on silica (eluant: ethyl acetatexe2x80x94cyclohexane 7-3) to obtain 7.49 g of the desired compound.